Eukaryotic cell numbers are regulated by a balance among proliferation, growth arrest, and apoptosis. Normal cells progress in a regulated fashion through successive stages of cellular growth and differentiation, culminating in growth arrest and apoptosis. Cells exposed to cytotoxic or genotoxic agents deviate from their regulated growth pattern by entering an altered growth stage or by undergoing premature cell death. This cellular response is dependent on specific gene products normally involved in differentiation and apoptosis pathways.
Cell exposed to DNA-damaging agents or differentiation-inducing agents express various genes including the myeloid differentiation primary response genes (MyD) and the growth arrest and DNA damage genes (gadd). Induction of these genes results in inhibition of DNA replication and growth arrest, restricting genetic changes that produce cellular transformation. Members of the MyD family are expressed during the differentiation of myeloid precursor cells into mature granulocytes and macrophages; gadd family members have been found in most cells examined (Liebermann, D. A. and Hoffmann, B. (1994) Stem Cells 12: 352-369).
The gadd genes were first isolated as UV irradiation induced transcripts from chinese hamster ovary cells. These genes are also induced by growth arrest treatments such as starvation and exposure to alkylating agents. The gadd153 and gadd45 genes are expressed and can be specifically induced with alkylating agents in almost all mammalian cells and tissues tested. The gadd153 is the hamster homologue of the human CHOP gene, which codes for a nuclear protein that serves as a dominant-negative inhibitor of the transcription factors C/EBP and LAP. Bacterially expressed CHOP inhibits the DNA-binding activity of C/EBP and LAP by forming heterodimers that cannot bind DNA. CHOP is found to be consistently rearranged in myxoid liposarcomas. GADD45 binds to proliferating cell nuclear antigen, a normal component of cyclin-dependent kinase complexes and a protein involved in DNA replication and repair. GADD45 stimulates DNA excision repair in vitro and inhibits entry of cells into S phase (Ron, D. and Habener, J. F. (1992) Genes Dev. 6: 439-453; Smith, M. L. et al (1994) Science 266: 1376-1380).
The MyD116 gene is the murine homolog of the hamster GADD34 gene. The MyD genes were first isolated from mouse leukemic myeloblasts following induction of terminal differentiation by stimulation with interleukin-6. Members of this gene family control cell growth and regulate cell differentiation by growth inhibition and induction of apoptosis. Activation of MyD116 genes induces myeloblastic leukemia cells to differentiate in vitro and reduces the aggressiveness of their leukemic phenotype in vivo (Lord, K. A. et al (1990) Nucleic Acids Res. 18: 2823; Lord, K. A. et al (1990) Cell Growth Differen. 1: 637-645; and Zhan, Q. et al (1994) Molec. Cell. Biol. 2361-2371).
The discovery of a new human growth regulator protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of cancer.